PROJECT SUMMARY/ABSTRACT Understanding aldosterone and cortisol regulation is essential for better understanding the pathophysiology of cardiovascular disease. This translational project stems from novel preclinical findings demonstrating a previously unknown regulatory pathway for aldosterone and cortisol at the level of the adrenal. Specifically, the mineralocorticoid receptor (MR) present on the adrenal cortex is part of a MR-mediated ultra-short feedback loop regulating aldosterone production and part of a MR-mediated inhibitory pathway regulating cortisol production. The goal of the proposed F32 project is to demonstrate the existence of these regulatory pathways in humans. The applicant will perform a 3-way cross-over study in which healthy participants will receive all three interventions, randomized on separate days: 1) placebo, 2) MR agonist (fludrocortisone), and 3) MR antagonist (eplerenone). Aldosterone and cortisol will be measured before and after direct adrenal stimulation with an infusion of AngII and cosyntropin (ACTH). The aims of the project are: 1) To test the hypothesis that there is an adrenal MR-mediated ultra-short feedback loop regulating aldosterone production in humans. As demonstrated in a preclinical model, the hypothesis in humans is: MR activation will decrease AngII-stimulated aldosterone production compared to placebo AND MR blockade will increase AngII-stimulated aldosterone production compared to placebo. 2) To test the hypothesis that there is an adrenal MR-mediated inhibitory pathway regulating cortisol production. As demonstrated in a preclinical model, the hypothesis in humans is: MR activation will decrease cosyntropin-stimulated cortisol production compared to placebo AND MR blockade will have no effect on cosyntropin-stimulated cortisol production compared to placebo. The results of the proposed research could greatly enhance understanding of aldosterone and cortisol regulation, and thus the pathogenesis of hypertension and cardiovascular disease. The training plan includes dedicated mentorship by Gail Adler, MD, PhD (sponsor), Gordon Williams, MD (specialty mentor in aldosterone), and Bernard Rosner, PhD (specialty mentor in biostatistics), each offering expertise tailored to the applicant?s needs and goals. Additionally, the applicant will complete formal training in clinical/translational investigation, clinical trial design, and statistics through a rigorous two-year Clinical/Translational Research Academy Certificate Program as well as dedicated coursework at the Harvard T.H. Chan School of Public Health. These activities will provide the applicant with the necessary tools critical for development toward a career as an independent clinical/translational researcher.